Background: Gluten-derived peptide antigens, administered intravenously, have been shown to induce tolerance, but systemic delivery of disease-relevant antigens can be associated with inflammation and limited tolerability. To improve tolerability while preserving tolerogenic efficacy, we developed VTP-1000, an intramuscularly administered nanoparticle co-delivering multiple gluten-derived peptide antigens with rapamycin.
Methods: The AVALON trial is a randomized, double-blind, placebo controlled, multicenter phase 1 study of VTP-1000. HLA-DQ2.5–positive adults with biopsy-confirmed CeD maintained on a gluten-free diet were enrolled into single-ascending-dose (SAD) or multiple-ascending-dose (MAD) cohorts spanning three escalating doses of VTP-1000. Subjects were randomized to VTP-1000 or placebo at 4:2 (SAD) and 6:2 (MAD). Upon completion of MAD dosing, participants underwent a gluten challenge with efficacy read-out.
Results: 42 CeD patients were enrolled into Avalon. Efficacy analyses of the 28 participants in MAD are ongoing. No treatment-related AEs greater than grade 2 were observed. Pharmacokinetic analyses indicated therapeutic rapamycin concentrations during antigen exposure were within therapeutic range. Pharmacodynamic assessments confirmed recognition of VTP-1000 gluten-derived peptides by T cells, with expected increases in serum IL-2. IL-2 levels across doses suggest antigen recognition without evidence of dose-dependent inflammatory activation.
Conclusion: VTP-1000 was safe and well tolerated. It induced immunologic responses consistent with immune recognition of antigen that was not dose-dependent and attenuated by rapamycin. The MAD portion of AVALON is ongoing.